Deep wound infection following total joint arthroplasty is a devastating complication for physician and patient, a leading cause of morbidity, and a significant economic burden to the healthcare system. With an aging population and increased life expectancies, the number of arthroplasties is expected to rise dramatically over the next 20 years. The growing number of high-risk patients undergoing surgery further increases the severity of septic complications and other adverse outcomes. Antibiotics have been incorporated into bone cement for prophylaxis and orthopedic applications for more than 30 years. However, antibiotic laden bone cement is not generally indicated for prophylactic use due to concerns about cost, long-term mechanical performance, and most importantly, the potential for developing antibiotic resistance. As an antimicrobial agent, silver has been extensively researched because of its exceptional safety and efficacy. Further, the risk of silver inducing widespread bacterial resistance is considered to be remote. Recently, the incorporation of silver nanoparticles (AgNP) into medical devices has been investigated, but problems encountered with homogeneously dispersing AgNPs into biomaterials and the need for complex processes and harsh chemicals required for synthesis have limited its use. Researchers at the University of Texas Health Science Center at San Antonio have recently developed an innovative single-step method to synthesize AgNPs in situ in acrylic resins such as polymethylmethacrylate (PMMA) that requires no harsh chemicals. Preliminary studies show that this material possesses mechanical properties comparable to resins without AgNPs, while demonstrating well-distributed AgNPs that provide extended release of Ag+ ions that are biocidal to several pathogens. Thus, the goal of this project is to develop a long-lasting, broad-spectrum, antimicrobial bone cement using this novel method to generate AgNPs in situ. This Phase I study has five Specific Aims: Specific Aim 1. Formulation and Evaluation of Mechanical Properties Specific Aim 2. In Vitro Ag+ Ion Release Specific Aim 3. In Vitro Antimicrobial Activity Specific Aim 4. Biocompatibility Specific Aim 5. Fatigue Testing PUBLIC HEALTH RELEVANCE: Infection following total knee and total hip replacement surgery is a devastating complication for patients and very costly to the healthcare system. Antibiotics can be incorporated into bone cement to reduce infection, but are generally not used preventively because they can adversely impact the mechanical properties of the cement, are expensive, and can cause drug resistance where a microorganism is able to survive exposure to the antibiotic. The development of a safe and effective antimicrobial bone cement containing silver nanoparticles that would not induce drug resistance and would overcome the limitations of current products would have a significant impact on public health.